Allylic chlorination process

ABSTRACT

This invention provides a novel allylic chlorination process for inserting a chlorine atom on the saturated methyl group of a 3-methyl-2-but-3-enoate group on the ring nitrogen atom of a 2-azetidinone or thiazolinoazetidinone. The chloro-substituted compounds prepared thereby are novel intermediates used in preparation of cephalosporins.

CROSS-REFERENCE

This application is a continuation-in-part of co-pending applicationSer. No. 34,825, filed Apr. 30, 1979, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention concerns the synthesis of antibiotic compounds of thecephalosporin series.

Azetidinones and thiazolinoazetidinones are now well known asintermediates for preparing cephalosporins. A variety of syntheticroutes have been published. In general, all of them proceed by firstopening the 5-membered ring of a penicillin to form athiazolinoazetidinone. The 5-membered ring of these compounds may beopened to form the corresponding azetidinone. Modifications are made tothe group on the nitrogen atom of the azetidinone ring (whether fused ornot) and the resulting compound is re-cyclized to form the desiredcephalosporin. The following publications are representative of thosewhich describe such processes: Belgian Pat. No. 864,321, Belgian Pat.No. 832,174, Belgian Pat. No. 862,793, Belgian Pat. No. 863,700, BelgianPat. No. 863,998, U.S. Pat. No. 4,079,181, U.S. Pat. No. 4,013,653, U.S.Pat. No. 4,077,970, British Pat. Nos. 1,472,863 through 1,472,870, andU.S. Pat. No. 4,018,776.

2. Prior Art

Some previous publications show or suggest halogenation of the butenoategroup on an azetidinone or thiazolinoazetidinone. Particular attentionis given to Belgian Pat. No. 862,793, where such a halogenation isperformed on a 3-methyl-2-but-3-enoate group. This patent, of May 2,1978, however, teaches generally that bromine, chlorine or iodine atomsmay be inserted with the use of free radical initiators.N-Bromosuccinimide in the presence of azobisisobutyronitrile isemphasized in the patent, although sulfuryl chloride and molecularchlorine are also used. The patent shows that the oxazolinoazetidinoneswhich are its starting compounds frequently have the oxazoline ringopened by the halogenation step, and that the methylbutenoate group isisomerized so that a mixture of products is obtained.

Belgian Pat. No. 864,321 shows the chlorination of a similar group on anoxazolinoazetidinone by molecular chlorine and strong light. However, asecond chlorine atom is also added on the 3-carbon atom.

U.S. Pat. No. 4,077,970 and British Pat. Nos. 1,472,863 through1,472,870 suggest the halogenation of a methylbutenoate group on athiazolinoazetidinone. However, the halogenations which these patentsshow cause the isomerization of the 3-butenoate group to a 2-butenoategroup.

SUMMARY OF THE INVENTION

The invention described here provides an allylic chlorination processwhich can cleanly insert a chlorine atom on the saturated methyl groupof a 3-methyl-2-but-3-enoate group on the ring nitrogen atom of a2-azetidinone ring. The process may be used on azetidinones as such, oron azetidinones which are fused with a thiazoline group. Thechloro-substituted compounds which are prepared by the use of thisprocess are novel intermediates which are useful in preparing antibioticcompounds of the cephalosporin series. The allylic chlorination of thisinvention proceeds in economical yields at moderate temperatures. Thechlorinating agents are molecular chlorine or t-butyl hypochlorite inany of a range of organic solvents, of which esters are preferred.

The particularly advantageous feature of the process of this inventionis its ability to chlorinate the 3-methyl-2-but-3-enoate group withoutundue isomerization of the group to the corresponding3-methyl-2-but-2-enoate group, or chlorinating the compound at any otherlocation.

Accordingly, the invention also provides novel compounds which were notaccessible prior to this invention. The novel compounds are of theformula ##STR1## wherein R is hydrogen,

methoxy,

C₁ -C₂ alkoxycarbonyl,

C₁ -C₈ alkyl,

C₁ -C₈ alkyl monosubstituted with protected hydroxy, C₁ -C₃ alkoxy orcyano,

C₂ -C₈ alkenyl,

C₂ -C₈ alkenyl monosubstituted with protected hydroxy, C₁ -C₃ alkoxy orcyano,

C₃ -C₈ cycloalkyl,

C₃ -C₈ cycloalkyl substituted with protected hydroxy, C₁ -C₃ alkoxy orcyano, ##STR2## R² is hydrogen, protected hydroxy, chloro, bromo, C₁ -C₃alkyl, C₁ -C₃ alkoxy, nitro or cyano;

Y is oxygen or a carbon-carbon bond;

R³ is protected hydroxy, C₁ -C₄ alkyl, or protected amino;

m is 0-2;

n is 0-2;

R¹ is a carboxylic acid protecting group; provided that the 1- and5-position C--H bonds in the thiazolinoazetidinone are in theα-position.

The novel compounds above are made by the novel process comprisingreacting a compound of the formula ##STR3## wherein the 1- and5-positions are in the configuration described above, with molecularchlorine or t-butyl hypochlorite in the presence of a C₁ -C₃ carboxylicacid; provided that, when the starting compound is athiazolinoazetidinone, and molecular chlorine is used, a hydrochloricacid scavenger is also present.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The ring systems which form the nuclei of the compounds discussed hereinwill be named according to Chemical Abstracts nomenclature. The ringsystems are numbered as follows. ##STR4## Thus, the fused-ring nucleusof a compound of this invention would be called a2-thia-4,7-diazabicyclo[3.2.0]hept-3-en-6-one.

It must be noted that the thiazolinoazetidinones of this invention, andtheir respective starting compounds, have the C₁ -H and C₅ -H bonds inthe α configuration. The thiazolinoazetidinone ring system is showngraphically as follows. ##STR5##

The various terms used in the descriptions above are used as theynormally are in organic chemistry. For example, the term C₁ -C₂alkoxycarbonyl includes methoxycarbonyl and ethoxycarbonyl.

The terms C₁ -C₈ alkyl, substituted C₂ -C₈ alkyl, C₂ -C₈ alkenyl,substituted C₂ -C₈ alkenyl, C₁ -C₃ alkoxy, C₁ -C₃ alkyl, C₁ -C₄ alkyl,C₄ -C₆ t-alkyl and C₄ -C₈ t-alkenyl include such groups as methyl,ethyl, isopropyl, hexyl, 2-ethylbutyl, neopentyl, octyl, 3-methylheptyl,4-octyl, t-butyl, 3-propyl-3-pentyl, formyloxymethyl,3-benzyloxtypentyl, 8-t-butoxyoctyl, 2-methoxyethyl, 6-propoxyhexyl,4-ethoxyoctyl, 3-cyanopropyl, cyanomethyl, 7-cyanoheptyl, vinyl, allyl,5-hexenyl, 1,1-dimethylallyl, 4-heptenyl, 2-octenyl,1-chloroacetoxyallyl, 5-formyloxy-3-pentenyl, 8-benzyloxy-4-octenyl,2-methoxyvinyl, 3-propoxyallyl, 8-ethoxy-2,6-octadienyl, 2-cyanoallyl,3-cyano-2-pentenyl, 8-cyano-4-octenyl, ethyl, methoxy, isopropoxy,2-butyl, 1,1-dimethylbutyl, 1,1-dimethyl-2-propenyl,1,1-dimethyl-3-hexenyl, and 1,1-diethyl-2-butenyl.

The terms C₃ -C₈ cycloalkyl and substituted C₃ -C₈ cycloalkyl includesuch groups as cyclopropyl, cyclopentyl, cycloheptyl, cyclooctyl,2-methoxymethoxycyclobutyl, 3-formyloxycyclohexyl,2-benzyloxycyclooctyl, 2-ethoxycyclopropyl, 2-methoxycyclohexyl,4-isopropoxycyclooctyl, 2-cyanocyclohexyl, 3-cyanocyclooctyl and2-cyanocyclopropyl.

The term protected amino refers to an amino group substituted with oneof the commonly employed amino-protecting groups such ast-butoxycarbonyl, benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl and1-carbomethoxy-2-propenyl. Other accepted amino-protecting groups suchas are described by J. W. Barton in Protective Groups in OrganicChemistry, J. F. W. McOmie, Editor, Plenum Press, New York, 1973,chapter 2 will be recognized by organic chemists as suitable for thepurpose.

The term, a carboxylic acid protecting group, refers to any group whichis conventionally used to block or protect the carboxylic acidfunctionality of a cephalosporin or penicillin while reactions involvingother functional sites are carried out. Such carboxylic acid protectinggroups are noted for their ease of cleavage and for their ability toprotect the acid from unwanted reactions. Such groups are thoroughlydescribed by E. Haslam in Protective Groups in Organic Chemistry,Chapter 5. Any such group may be used, of course. The preferred groups,however, are C₁ -C₄ alkyl, C₄ -C₆ t-alkyl, C₅ -C₈ t-alkenyl, benzyl,methoxybenzyl, nitrobenzyl, diphenylmethyl, phthalimidomethyl,succinimidomethyl or trichloroethyl.

Similarly, the term protected hydroxy refers to groups formed with ahydroxy group such as formyloxy, 2-chloroacetoxy, benzyloxy,diphenylmethoxy, triphenylmethoxy, 4-nitrobenzyloxy, trimethylsilyloxy,phenoxycarbonyloxy, t-butoxy, methoxymethoxy and tetrahydropyranyloxy.Other accepted hydroxy-protecting groups, such as those described by C.B. Reese in Chapter 3 of Protective Groups in Organic Chemistry will beunderstood to be included in the term protected hydroxy.

It is believed that the above formulae and discussion are adequate todefine completely the novel compounds provided by this invention.However, in order to assure that anyone of skill in organic chemistrycan obtain the compounds, the following group of exemplary compounds arementioned.

methyl2-(4-chloro-3-formamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

ethyl2-(4-chloro-3-methoxyformamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

isopropyl2-(4-chloro-3-methoxyoxalylamino-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

butyl2-(4-chloro-3-acetamido-2-oxo-2-azetidinyl)-3-chloromethyl-3-butenoate

t-butyl2-(4-chloro-3-propionamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

1,1-dimethylpropyl2-[4-chloro-3-(2-methylpropionamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

1,1-dimethylallyl2-[4-chloro-3-(2-methylbutyramido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

1,1-diethyl-2-butenyl2-[4-chloro-3-(2-ethylvaleramido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-(4-chloro-3-nonanamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

3-methoxybenzyl2-[4-chloro-3-(3-formyloxypropionamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-(4-benzyloxyhexanamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

3-nitrobenzyl2-[4-chloro-3-(9-chloroacetoxynonanamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-(4-chloro-3-methoxyacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

phthalimidomethyl2-[4-chloro-3-(6-propoxyhexanamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

succinimidomethyl2-[4-chloro-3-(4-ethoxynonanamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl2-[4-chloro-3-(2-cyanopropionamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

t-butyl2-[4-chloro-3-(5-cyanovaleramido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-(8-cyanooctanamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-(3-butenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

methyl2-[4-chloro-3-(5-hexenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

3-nitrobenzyl2-[4-chloro-3-(8-nonenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

ethyl2-[4-chloro-3-(3-methoxymethoxy-3-butenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

t-butyl2-[4-chloro-3-(5-formyloxy-3-pentenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-(8-trimethylsilyloxy-3,6-nonadienamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

isopropyl2-[4-chloro-3-(3-methoxy-2-propenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-(3-ethoxy-3-pentenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

3-methoxybenzyl2-[4-chloro-3-(9-propoxy-3-nonenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

methyl2-[4-chloro-3-(3-cyano-3-butenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

trimethylsilyl2-[4-chloro-3-(6-cyano-2-hexenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-methoxybenzyl2-[4-chloro-3-(5-cyano-2-nonenamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

succinimidomethyl2-(4-chloro-3-cyclopropylformamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

diphenylmethyl2-(4-chloro-3-cyclopentylformamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl2-(4-chloro-3-cyclohexylformamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

t-butyl2-(4-chloro-3-cyclooctylformamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-(2-benzyloxycyclobutylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[(4-chloro-3-(4-formyloxycyclohexylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-diphenylmethoxycyclooctylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

3-nitrobenzyl2-[4-chloro-3-(2-methoxycyclooctylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-(3-ethoxycycloheptylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl2-[4-chloro-3-(3-propoxycyclopentylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

succinimidomethyl2-[4-chloro-3-(2-methoxycyclopropylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-(2-cyanocyclobutylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

triphenylmethyl2-[4-chloro-3-(3-cyanocyclohexylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-(4-cyanocyclooctylformamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

methyl2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

4-nitrobenzyl2-(4-chloro-3-phenylacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-(4-formyloxybenzyloxyacetamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl2-[4-chloro-3-[3-(3-chloroacetoxyphenyl)propionamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-[2-(2-benzyloxyphenyl)ethoxyacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-[3-[2-(4-diphenylmethoxyphenyl)ethoxy]propionamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

triphenylmethyl2-[4-chloro-3-(3-triphenylmethoxybenzyloxyacetamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-methoxybenzyl2-[4-chloro-3-[2-trimethylsilyloxy-2-[4-(4-nitrobenzyloxy)phenyl]acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

methyl2-[4-chloro-3-[2-(t-butoxy)-2-(2-phenoxycarbonyloxyphenyl)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-[2-tetrahydropyranyloxy-2-(3-methoxymethoxyphenyl)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-methoxybenzyl2-[4-chloro-3-[2-(t-butoxyformamido)-2-(4-chlorophenyl)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

phthalimidomethyl2-[4-chloro-3-[2-benzyloxyformamido-2-(3-bromophenyl)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-[2-(2-methylphenyl)-2-(4-methoxybenzyloxyformamido)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-[2-(4-ethylphenyl)-2-(4-nitrobenzyloxyformamido)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-methoxybenzyl2-[4-chloro-3-[2-(3-propylphenyl)-2-(2,2,2-trichloroethoxyformamido)acetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

t-butyl2-[4-chloro-3-[2-(4-methoxyphenoxy)-2,2-dimethylacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

triphenylmethyl2-[4-chloro-3-[2-(3-isopropoxyphenoxy)-2,2-dimethylacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

benzyl2-[4-chloro-3-[2-(2-nitrophenoxy)-2,2-dimethylacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

methyl2-[4-chloro-3-[2-(4-cyanophenoxy)-2,2-dimethylacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

ethyl(1α,5α)-2-(3-methoxy-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

isopropyl(1α,5α)-2-(3-ethoxycarbonyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl (1α,5α)-2-(3-ethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

phthalimidomethyl(1α,5α)-2-[3-(2-butyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-(3-hexyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-[3-(3-formyloxypentyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-methoxybenzyl(1α,5α)-2-[3-(2-benzyloxyoctyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

benzyl(1α,5α)-2-[3-(3-propoxypentyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

1,1-diethyl-2-butenyl(1α,5α)-2-[3-(1-cyanoethyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

1,1-dimethylallyl(1α,5α)-2-[3-(5-ethoxyheptyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

1,1-dimethylpropyl(1α,5α)-2-[3-(3-cyanobutyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

butyl(1α,5α)-2-(3-vinyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-(3-pentenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-(3-triphenylmethoxy-2-butenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

benzyl(1α,5α)-2-[3-(7-trimethylsilyloxy-2,6-octadienyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-methoxybenzyl(1α,5α)-2-[3-(2-methoxyvinyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-[3-(3-ethoxy-3-butenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

t-butyl(1α,5α)-2-[3-(3-cyanoallyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-methoxybenzyl(1α,5α)-2-[3-(6-cyano-2-octenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl(1α,5α)-2-(3-cyclopropyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-(3-cyclohexyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

t-butyl(1α,5α)-2-[3-(3-phenoxycarbonyloxycyclobutyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-(3-benzyloxycyclopentyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-(4-methoxycyclooctyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-(3-propoxycyclohexyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl(1α,5α)-2-[3-(2-ethoxycyclopropyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-[3-(3-cyanocyclobutyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-(5-cyanocyclooctyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

phthalimidomethyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

succinimidomethyl(1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-[2-(3-chloroacetoxyphenyl)ethyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-methoxybenzyl(1α,5α)-2-[3-[2-(3-benzyloxyphenyl)ethoxymethyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

benzyl(1α,5α)-2-[3-[2-[2-(4-diphenylmethoxyphenyl)ethoxy]ethyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-nitrobenzyl(1α,5α)-2-[3-[α-trimethylsilyloxy-4-(4-nitrobenzyloxy)benzyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-(α-tetrahydropyranyloxy-4-methoxymethoxybenzyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-nitrobenzyl(1α,5α)-2-[3-[α-(t-butoxyformamido)-3-chlorobenzyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-(α-benzyloxyformamido)-3-bromobenzyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

methyl(1α,5α)-2-[3-[α-(4-nitrobenzyloxyformamido)-3-ethylbenzyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-[α-(2,2,2-trichloroethoxyformamido)-4-propylbenzyl]-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

t-butyl(1α,5α)-2-[3-(α,α-dimethyl-4-methoxyphenoxymethyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

3-methoxybenzyl(1α,5α)-2-[3-(α,α-dimethyl-2-isopropoxyphenoxymethyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

2,2,2-trichloroethyl(1α,5α)-2-[3-(α,α-dimethyl-4-cyanophenoxymethyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

benzyl2-(4-chloro-3-benzamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

trimethylsilyl2-[4-chloro-3-(3-methylbenzamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-(2-ethoxybenzamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-(3-phenyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

benzyl(1α,5α)-2-[3-(α-methylbenzyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-methoxybenzyl(1α,5α)-2-[3-(4-chloro-α-butylbenzyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

isopropyl2-[4-chloro-3-[2-(4-cyanophenyl)-2-ethylacetamido]-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

The preferred novel compounds of this invention are the compoundswherein R and R¹ are groups derived from the corresponding groups ofreadily available penicillins. Thus, the most highly preferred compoundsof this invention are those wherein R is benzyl, phenyl, p-tolyl orphenoxymethyl, and R¹ is 4-nitrobenzyl, 4-methoxybenzyl, diphenylmethyl,benzyl or 2,2,2-trichloroethyl.

The azetidinones of this invention constitute one preferred class; thethiazolinoazetidinones constitute the most preferred class of compoundsof this invention.

Thus, the following group of compounds represents most particularlypreferred individual compounds of this invention.

4-nitrobenzyl2-(4-chloro-3-phenylacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

diphenylmethyl2-(4-chloro-3-phenylacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-(4-methylbenzamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-(4-methylbenzamido)-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl2-[4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

diphenylmethyl2-[4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-[3-(4-methylphenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-[3-(4-methylphenyl)-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl]-3-chloromethyl-3-butenoate

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

diphenylmethyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of this invention, by which are made the novel compounds ofthis invention, proceeds in a single step by contacting and reacting thestarting compounds described above with either molecular chlorine or,preferably, t-butyl hypochlorite. A small amount of a C₁ -C₃ carboxylicacid in the reaction mixture is needed.

The choice of solvent in which to run the reaction is not critical. Thepreferred solvents are the C₂ -C₈ alkyl esters, such as ethyl acetate,ethyl formate, methyl acetate, butyl acetate, methyl formate, and thelike. The esters are especially advantageous, because they ordinarilycontain a small amount of free carboxylic acid which is sufficient toserve as the reaction initiator. However, many other solvents includingketones including acetone and methyl ethyl ketone, halogenated solventssuch as dichloromethane, chloroform, 1,1-dichloroethane, chlorobenzene,bromobenzene and the like, acids including acetic acid and propionicacid, nitriles such as acetonitrile, and nitroalkanes such asnitromethane, are effectively used.

When the starting compound is a thiazolinoazetidinone, and molecularchlorine is used, it is necessary to include a hydrochloric acidscavenger in the reaction mixture, because free hydrochloric acid islikely to cause chlorination at the 3-position. Epoxides, especiallypropylene oxide and butylene oxide, are the preferred acid scavengers.Other basic compounds may also be used, however, especially basic saltssuch as the alkali metal salts of carboxylic acids, including sodium andpotassium salts of formic and acetic acids. Still other bases, includinginorganic bases such as the hydroxides, carbonates and bicarbonates ofsodium, potassium and lithium, may also be used as acid scavengers.

The process of this invention proceeds in acceptable yields atconvenient temperatures in the range of from about -20° C. to about 50°C.; the preferred temperature range is from about -10° C. to the ambienttemperature.

The process of this invention gives excellent yields of the novelcompounds of this invention. However, a certain amount of thecorresponding 3-chloromethyl-2-butenoate is usually produced as a sideproduct. This process usually gives about 4 parts of the desired novelcompound and 1 part of the 2-butenoate.

The starting compounds used in the process of this invention are nowknown in the cephalosporin art. The thiazolinoazetidinones are mosteasily prepared as described by Cooper, U.S. Pat. No. 3,705,892, whichillustrates the reaction of a penicillin sulfoxide with atrialkylphosphite or triphenylphosphine to prepare the desired startingthiazolinoazetidinone in a single step, in the 1α,5α epimeric form. Thereaction is also discussed by Cooper and Spry in chapter 5 ofCephalosporins and Penicillins, Flynn, Editor, Academic Press, New York,1972, at page 235.

The starting azetidinones are prepared as illustrated, for example, inU.S. Pat. No. 4,013,653, of Wolfe, and U.S. Pat. No. 3,860,577, ofKukolja. Kukolja shows that a penicillin can be reacted with achlorinating agent to prepare an azetidinone in a single step. Kukolja'sazetidinones have the side chain on the nitrogen atom in the form of a2-butenoate rather than a 3-butenoate. The starting azetidinones used inthe present process are obtained from the azetidinones of Kukolja asshown by Wolfe, supra, who brominates both of the terminal methyl groupsof Kukolja's product, and then debrominates with zinc and an alkanoicacid to obtain the desired azetidinyl-3-butenoate which is a startingcompound for the process of this invention.

The R groups of the starting compounds are derived from thecorresponding 6-amido groups of the penicillin which is the ultimatestarting compound. It will be recognized that the R groups are thosewhich have been commonly seen on penicillin and cephalosporinantibiotics of the prior art. Antibiotic chemists will understand thatthe R groups of the starting compounds used in this invention areprovided, in many cases, by deacylating the penicillin which is theultimate starting compound, and reacylating with the desired group. Suchsteps are very old in the antibiotic art, of course, and have been welldiscussed by Kaiser and Kukolja in Chapter 3 of Cephalosporins andPenicillins, cited supra.

The following preparative examples are presented to assure that organicchemists can easily obtain any compound of this invention, and can carryout any process of this invention. The products of the examples wereidentified by various instrumental analytical techniques, as will beexplained in the individual examples. When a given product was maderepeatedly by different embodiments of the process of this invention,the product was often identified by thin-layer chromatography (TLC) ornuclear magnetic resonance analysis (NMR) as identical to the originalsample, and was therefore not isolated or further analyzed.

EXAMPLE 1 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 5.83 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 100 ml. of chloroform, and 4.1 g. of sodium acetate and4.3 ml. of acetic acid were added. The mixture was stirred and cooled to-10° C. A 2.71 g. portion of t-butyl hypochlorite was dissolved in 5 ml.of chloroform and added to the reaction mixture over a period of 10minutes. The reaction mixture was stirred at constant temperature for 2hours, and was then poured into saturated aqueous sodium chloridesolution. The organic layer was separated, extracted twice with portionsof fresh brine and dried over magnesium sulfate. The dry organic layerwas then evaporated under vacuum to obtain 6.5 g. of a light yellow oilwhich was purified by high pressure liquid chromatography, using amixture of 15 parts of dichloromethane and 1 part of ethyl acetate asthe eluting solvent. The product-containing fractions were combined andheated in methanol, whereupon crystallization began. A total of 2.34 g.of the desired product, m.p. 105.5°-107° C., was obtained.

Infrared analysis of the product, as a potassium bromide compact, showedmaxima at 1795, 1787, 1770, 1755 and 1740 cm₋₁. Ultraviolet analysis inmethanol showed a lambda-maximum at 262 nm, ε 11,742.

Nuclear magnetic resonance analysis in CDC1₃ on a 360 megacycleinstrument showed the following δ values: 3.9 (q, J=12Hz); 4.94 (q,J=14Hz); 5.12(s); 5.23(s); 5.46(s); 5.88(d,J=4Hz); 6.04 (d, J=4Hz); 5.29(q, J=14Hz); 6.88-7.33(m); 7.48(d, J=8Hz); 8.23(d, J=8Hz)

EXAMPLE 2

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 4.67 g. portion of (1α,5α)-2-(3-phenoxy-methyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in 250 ml. of ethyl acetate,and 10 ml. of propylene oxide was added. The mixture was stirred at roomtemperature while a solution of 0.35 g. of chlorine in carbontetrachloride was added, and the mixture was stirred for 1 hour more.Successively, two additional 0.35 g. portions of chlorine were added,and the mixture was then cooled to 0° C. A fourth portion of chlorinewas added, and the mixture was allowed to stand for 16 hours. Thereaction mixture was then evaporated, and the resulting oil was purifiedby preparative thin-layer chromatography. The product-containingfractions were combined and evaporated to dryness to isolate the desiredproduct as a pale yellow foam, which was identified as identical to theproduct of Example 1.

EXAMPLE 3

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 920 mg. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-butenoatewas dissolved in 50 ml. of t-butyl acetate, and 0.07 g. of chlorine and1 ml. of propylene oxide were added. The reaction was stirred at roomtemperature for 1 hour, and the reaction mixture was examined by nuclearmagnetic resonance analysis. Signals indicating the presence of thedesired product were observed.

EXAMPLE 4

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 3 was followed, except that methyl formate wasused as the solvent. NMR analysis of the reaction mixture indicated thepresence of the desired product, which was not isolated.

EXAMPLE 5

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 3 was repeated again, using dichloromethane asthe solvent. Again NMR analysis of the reaction mixture showed that thedesired product was obtained, although it was not isolated.

EXAMPLE 6

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 920 mg. portion of 4nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 50 ml. of methyl formate, and 1 ml. of propylene oxideand 0.2 g. of t-butyl hypochlorite were added. The reaction mixture wasstirred for 1 hour at room temperature, at which time the reactionmixture was examined by NMR analysis, which showed the presence of alarge amount of the desired product. The reaction mixture was evaporatedunder vacuum, and the residue was crystallized from methanol/diethylether to obtain 350 mg. of the desired product, identical to the productof Example 1.

EXAMPLE 7

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 3 was followed, except that sodium carbonate wasused as the hydrochloric acid scavenger instead of propylene oxide. NMRanalysis of the reaction mixture after 1 hour showed the presence of thedesired product, which was not isolated.

EXAMPLE 8

4-nitrobenzyl (1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 450 mg. portion of 4-nitrobenzyl (1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-butenoatewas dissolved in 50 ml. of methyl formate, and 0.5 ml. of propyleneoxide was added. An 0.15 ml. portion of t-butyl hypochlorite was added,and the reaction mixture was stirred for 1 hour at room temperature. NMRanalysis of the reaction mixture in CDC1₃ on a 60 megacycle instrumentshowed the presence of the desired product, which was not isolated. 3.6(q, J=14Hz); 3.84(s); 5.1(s); 5.25(s); 5.4(s); 5.86 (broad s); 7.28(s);7.48 (d, J=8Hz); 8.16 (d, J=8Hz)

EXAMPLE 9

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 9.6 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 250 ml. of methyl formate and a 10 ml. portion ofpropylene oxide was added. The reaction mixture was stirred at 0° C.,while a total of 4 ml. of t-butyl hypochlorite was added in 5 portionsat intervals of approximately 5 minutes. Analysis of the reactionmixture by high pressure liquid chromatography showed that the amount ofthe desired product in the reaction mixture increased steadily with eachaddition of the hypochlorite, and that essentially complete conversionto the desired product occurred. The product was identified as identicalto the product of Example 1.

EXAMPLE 10

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of methyl formate and 2 ml. of propylene oxideat room temperature. A 2.5 ml. portion of 1-molar chlorine solution incarbon tetrachloride was added dropwise over a 30 minute period. Afterthe mixture had stood for 1.5 hours, an additional 2.5 ml. of thechlorine solution was added, and the reaction mixture was checked bythin-layer chromatography. An additional 1 ml. of chlorine solution wasadded, and the mixture was allowed to stand at room temperature for 16hours. The mixture was then evaporated to dryness, and the residue wastaken up in dichloromethane and precipitated by the addition of heptane.Analysis of the product by NMR showed that it was identical to theproduct of Example 1, although some impurities were present.

EXAMPLE 11

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of methyl formate, 170 mg. of sodium formate wasadded, and the mixture was cooled to -13° C. Six 0.1 ml. portions oft-butyl hypochlorite were added at intervals of about 5 minutes, whilethe temperature of the mixture rose to -3° C. NMR analysis of thereaction mixture showed that the reaction had gone essentially tocompletion and that the desired product was the major component of thereaction mixture.

EXAMPLE 12

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 11 was followed, except that 210 mg. of potassiumformate was used as the base, and a few milligrams of 18-crown-6 wasalso added. The temperature of the reaction was from -1° C. to 8° C.Again, NMR analysis of the reaction mixture showed that the reaction hadgiven an essentially complete yield of the desired product, identical tothe product of Example 1.

EXAMPLE 13

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of methyl formate and cooled in an ice-methanolbath. A 680 mg. portion of sodium formate and 0.18 ml. of formic acidwere added, and 0.6 ml. of t-butyl hypochlorite was added in 0.1 ml.portions while the temperature of the reaction mixture rose from -8° C.to -2° C. The mixture was stirred for a total of about 1.5 hours, whilethe temperature rose to 6° C. NMR analysis of the reaction mixtureshowed the presence of the desired product, identical to the product ofExample 1.

EXAMPLE 14

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3en-7-yl)-3chloromethyl-3-butenoate

The process of Example 13 was followed, except that the solvent wasdichloromethane instead of methyl formate. The final reactiontemperature was -1° C. in this instance. NMR analysis of the reactionmixture showed that somewhat less of the desired product was obtainedand that the reaction mixture still contained some starting compound.

EXAMPLE 15

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of dichloromethane and cooled. An 0.38 ml.portion of formic acid and 0.81 ml. of pyridine were added to thereaction mixture, and 0.6 ml. of t-butyl hypochlorite was addedportionwise while the temperature of the reaction mixture rose from -14°C. to -2° C. Analysis of the reaction mixture after about 1.5 hoursshowed that a moderate yield of the desired product, identical to theproduct of Example 1, was obtained.

EXAMPLE 16

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 13 was followed, except that the solvent was amixture of 10 ml. of dichloromethane and 10 ml. of methyl acetate. Theinitial reaction temperature was -14° C., rising to -3° C. The mixturewas stirred for about 1 hour, and was then evaporated under vacuum todryness. The residue was purified over silica gel, using as solvent amixture of 15 parts of dichloromethane and 1 part ethyl acetate.Analysis of the fractions removed from the column showed that the majorproduct was the desired one, and that the corresponding3-chloromethyl-2-butenoate was a minor product.

EXAMPLE 17

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo-[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 10 ml. of methyl acetate and 10 ml. of dichloromethane,and the solution was cooled. An 0.5 ml. portion of acetic acid and 0.8g. of sodium acetate were added to the reaction mixture, followed by 0.6ml. of t-butyl hypochlorite in 0.1 ml. portions. The temperature of themixture ranged from -5° C. to 3° C. during the addition. After 1 hour ofstirring, the reaction mixture was evaporated to dryness under vacuum,and the residue was purified by chromatography over an 8-cm. column ofsilica gel, using the same eluting solvent as used in Example 16. Themajor product was the desired one, identical to the product of Example1.

EXAMPLE 18

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 13 was carried out again, but without the formicacid, in order to ascertain the importance of the acid. Analysis of thereaction mixture by thin-layer chromatography at intervals showed thatthe reaction produced the desired product, but at a slower rate. Evenafter 5 days of standing at ambient temperature, the reaction was notcomplete.

EXAMPLE 19

4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

An 0.26 ml. portion of 50 percent aqueous sodium hydroxide solution wasadded to 30 ml. of methyl formate with stirring. After about 20 minutes,1.17 g. of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoateand 3 ml. of dichloromethane were added, and the reaction mixture wascooled. An 0.6 ml. portion of t-butyl hypochlorite was added in 0.1 ml.portions while the temperature rose from -5° C. to 0° C. After themixture had stirred for 1 hour, it was analyzed by NMR and TLC, whichanalysis indicated that the desired product, identical to the product ofExample 1, had been obtained.

EXAMPLE 20 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 17 was repeated, except that the solvent was 20ml. of acetone, and the reaction temperature ranged from -10° C. to 1°C. Analysis by NMR and TLC showed that the desired product, identical tothe product of Example 1, was obtained.

EXAMPLE 21 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 20 was repeated, except that the solvent was 25ml. of 1,2-dichloroethane. Analysis of the reaction mixture by TLC andNMR methods showed that a yield of the desired product, identical to theproduct of Example 1, was obtained.

EXAMPLE 22 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 20 ml. of 1,2-dichloroethane and the solution wascooled. A 1.14 ml. portion of acetic acid and 0.53 g. of sodiumcarbonate were added to the mixture, and 0.6 ml. of t-butyl hypochloritewas added in 0.1 ml. portions over a period of 1 hour while thetemperature varied from -8° C. to 4° C. TLC analysis indicated that agood yield of the desired product, identical to the product of Example1, was obtained.

EXAMPLE 23 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 20 ml. of chloroform, and the solution was cooled. Then0.34 g. of sodium formate and 0.19 ml. of formic acid were added,followed by six 0.1 ml. aliquots of t-butyl hypochlorite over a periodof 70 minutes while the temperature rose from -10° C. to -1° C. TLCindicated that the reaction produced the desired compound, identical tothe product of Example 1.

EXAMPLE 24 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in chloroform and the solution was cooled. An 0.82 g.portion of sodium acetate and 0.57 ml of acetic acid were added,followed by 0.6 ml. of t-butyl hypochlorite in six 0.1 ml. portions overa period of 70 minutes while the temperature rose from -14° C. to -1° C.TLC analysis after 3 hours showed that the desired product, identical tothe product of Example 1, was obtained.

EXAMPLE 25 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in chloroform and the mixture was cooled. Then 0.38 ml. ofpropionic acid and 0.48 g. of sodium propionate were added, and 0.6 ml.of t-butyl hypochlorite was added in the usual manner. The temperaturevaried from -15° C. to -3° C. over the 1-hour period of the additions.TLC analysis showed that the reaction produced a relatively small yieldof the desired product after 75 minutes.

EXAMPLE 26 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 24 was repeated, except that the hypochlorite wasadded in one portion, when the temperature of the reaction mixture was-12° C. After 100 minutes, the temperature had risen to 9° C., and thecourse of the reaction was checked by TLC and NMR analysis, whichindicated that the reaction was not complete but that the desiredcompound was obtained.

EXAMPLE 27 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in 20 ml. of chloroformand the solution was cooled. A 1.14 ml. portion of acetic acid and 0.82g. of sodium acetate were added, and 3.5 ml. of 1-molar chlorinesolution in carbon tetrachloride was added dropwise over a period of 5minutes. The reaction temperature was -14° C. The mixture was stirredfor 2 hours, and was then analyzed by TLC and NMR methods. Anapproximately 50 percent yield of the desired product, identical to theproduct of Example 1, was obtained.

EXAMPLE 28 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

4.68 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 100 ml. of methyl formate and 5 ml. of butylene oxidewas added, followed by 1.09 g. of t-butyl hypochlorite. The mixture wasstirred at ambient temperature for 1 hour, after which an additional 0.3ml. of the hypochlorite was added, and the mixture was stirred for 1hour more. The reaction mixture was then poured into heptane, and wasevaporated to an oil under vacuum. The residue was taken up indichloromethane, filtered, and evaporated to dryness. The residue wasthen taken up in dichloromethane again, and purified by chromatographyover silica gel. The product-containing fractions were analyzed by TLCand NMR methods, which indicated that the desired product, identical tothe product of Example 1, was obtained.

EXAMPLE 29 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

An 0.46 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of acetonitrile at ambient temperature, and 0.12ml. of t-butyl hypochlorite was added. The mixture was allowed to standfor 4 hours, after which analysis by TLC and NMR indicated that a yieldof about 20 percent of the desired product, identical to the product inExample 1, had been obtained.

EXAMPLE 30 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 29 was repeated, using nitromethane as thesolvent. After one-half hour of standing, the reaction produced about 25percent of the desired product, as indicated by TLC and NMR analysis.

EXAMPLE 31 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 0.46 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-butenoatewas dissolved in 50 ml. of t-butyl acetate and 2 drops of formic acidwas added. A 1 ml. portion of t-butyl hypochlorite was added in 1portion and the mixture was stirred at room temperature for 16 hours.Analysis by TLC and NMR showed that a yield of the desired product wasobtained.

EXAMPLE 32 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoate was dissolved in 35 ml. ofmethyl formate, and the reaction mixture was cooled to -10° C. Then 0.6ml. of t-butyl hypochlorite was added in 0.05 ml. aliquots at intervalsof 5 minutes, while the temperature rose to -3° C. Analysis by TLC andNMR showed that a good yield of the desired product was obtained.

EXAMPLE 33 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 32 was repeated, except that the solvent wasethyl formate. The result of this experiment was similar to the resultof the experiment of Example 32, in that a good yield of the desiredproduct, identical to the product of Example 1, was obtained.

EXAMPLE 34 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 35 ml. of distilled methyl acetate. An 0.6 ml. portionof t-butyl hypochlorite was added in the same portionwise fashion usedin Example 32, while the temperature varied from -20° C. to -6° C.Analysis by TLC and NMR showed that no reaction had occurred.

One drop of formic acid was added, followed by a further 0.6 ml. of thehypochlorite in 0.05 ml. aliquots at 5 minute intervals at temperaturesfrom -5° C. to 2° C. Analysis by TLC and NMR showed this time that thedesired product, identical to the product of Example 1, was obtained.

EXAMPLE 35 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 30 ml. of distilled methyl acetate and cooled. Then afew drops of trifluoroacetic acid were added, followed by 1.2 ml. oft-butyl hypochlorite over a period of 2 hours at temperatures from -5°C. to 1° C. Analysis by TLC and NMR showed approximately a 50 percentyield of the desired product, identical to the product of Example 1.

EXAMPLE 36 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of distilled methyl formate, and the solutionwas cooled. An 0.1 ml. portion of formic acid was added, followed by 0.6ml. of t-butyl hypochlorite in 0.05 ml. aliquots over a period of 1 hourat temperatures from -13° C. to -3° C. Analysis by TLC and NMR showedthat the desired product, identical to the product of Example 1, wasobtained.

EXAMPLE 37 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of methyl formate, 0.1 ml. of dimethylformamidewas added, and the solution was cooled. An 0.6 ml. portion of t-butylhypochlorite was added in the same manner used in Example 36, while thetemperature varied from -3° C. to 1° C. The desired product was obtainedas indicated by TLC and NMR analysis.

EXAMPLE 38 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

The process of Example 37 was repeated, except that an 0.1 ml. portionof formic acid was added, and the temperature varied between -11° C. and2° C. TLC and NMR analysis indicated that the desired product, identicalto the product of Example 1, was obtained.

EXAMPLE 39 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 1.17 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 25 ml. of methyl formate and 1 ml. of trimethylorthoformate. The solution was cooled, and five 0.1 ml. aliquots oft-butyl hypochlorite were added over a period of 40 minutes attemperatures from -4° C. to 1° C. After 80 minutes, the mixture wasanalyzed by TLC and NMR methods, which showed that the desired product,identical to the product of Example 1, had been obtained.

EXAMPLE 40 4-nitrobenzyl(1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 0.45 g. portion of 4-nitrobenzyl(1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 50 ml. of methyl formate, and 0.1 ml. of t-butylhypochlorite was added. The mixture was allowed to stand at ambienttemperature for 3 hours, and was then analyzed by NMR, which showed thatthe desired product, identical to the product of Example 8, had beenobtained.

EXAMPLE 41 benzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate

A 0.42 g. portion of benzyl(1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]-hept-3-en-7-yl)-3-methyl-3-butenoatewas dissolved in 50 ml. of methyl formate, and 1 ml. of propylene oxidewas added. The mixture was cooled to 0° C., and 0.15 ml. of t-butylhypochlorite was added in 1 portion. The mixture stood for 30 minutes at0° C., at which time analysis by nuclear magnetic resonance in CDCl₃ ona 60 megacycle instrument showed that the desired product had beenobtained. 3.95(s); 4.85(s); 5.2 (broad s); 5.4(s); 5.8 (d, J=4Hz);5.92(d, J=4Hz); 6.8-7.5(m)

EXAMPLE 42 diphenylmethyl2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

A 5.18 g. portion of diphenylmethyl2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-methyl-3-butenoatewas dissolved in 200 ml. of methyl formate, and 1.71 ml. of t-butylhypochlorite was added. The mixture was stirred at room temperature for16 hours. It was then evaporated under vacuum to obtain a white foam,which was taken up in ethyl acetate and washed three times with water.The organic layer was then decolorized with activated carbon, dried overmagnesium sulfate, and evaporated to a white foam. The foam was taken upin 100 ml. of dry diethyl ether, from which 1.12 g. of the desiredproduct was obtained in crystalline form. The product was analyzed byinfrared in chloroform, showing maxima at 1795, 1745 and 1695 cm⁻¹ ; asecond spectrum in methanol showed maxima at 1775, 1740 and 1695 cm⁻¹.NMR analysis on a 100 megacycle instrument in CDCl₃ showed the followingδ values. 4.24(s); 4.63(s); 5.73(center of q); 6.2(d); 5.09(s); 5.33(s);5.5(s)

EXAMPLE 43 diphenylmethyl2-(4-chloro-3-phenoxyacetamido-2-oxo-1-azetidinyl)-3-chloromethyl-3-butenoate

The process of Example 42 was repeated, on a scale twice as large, andquenching the reaction after two and one-half hours. Workup as performedin Example 42 provided 3.73 g. of the desired product, identical to theproduct of Example 42 by TLC and NMR analysis.

The novel compounds which have been described are used as intermediatesin the preparation of cephalosporins and oxa-beta-lactams. Theazetidinones of this invention are converted to thethiazolinoazetidinones of this invention by a step which was describedby Kukolja and Lammert, U.S. Pat. No. 3,832,347. The azetidinone isfirst reacted with a halogenating agent such as phosphorus pentachlorideto form the imino halide of the --NHCOR side chain. The imino halide isthen reacted with hydrogen sulfide or a thioalkanoyl compound to preparethe thiazolinoazetidinone, having the unchanged 3-butenoate group, ofthis invention.

The thiazolinoazetidinones are used in various processes, one of whichwas described by Masi et al., U.S. Pat. No. 4,035,362. The compound isfirst treated with mild base, such as pyridine in an organic solvent, toconvert the 3-butenoate group to a 2-butenoate group. The compound isthen reacted with an azoderivative such as ethyl azodicarboxylate, whichopens the thiazoline ring and forms an azetidinone having a4-hydrazinothio group. That intermediate is reacted with a strong basein an anhydrous organic solvent to form a 3-chloromethyl-3-cephem, auseful intermediate for preparing cephalosporin antibiotics.

A preferred use of this invention is the preparation of3-hydroxycephalosporins from the thiazolinoazetidinones of thisinvention. The reaction which prepares the 3-hydroxycephalosporins isreadily performed as follows. The thiazolinoazetidinone is first reactedwith ozone, in an inert solvent. The reaction is carried out at atemperature from about -100° C. to about 0° C., preferably at atemperature from about -80° C. to about -20° C. The ozonolysis may bedone in any of many solvents including the halogenated hydrocarbons,such as chloroform, dichloromethane, 1,2-dichloroethane, bromoethane,carbon tetrachloride and the like. Ethers such as diethyl ether,tetrahydrofuran, diethylene glycol dimethyl ether, methyl ethyl etherand the like are likewise suitable. Further, alkanes such as hexane andoctane, amides such as dimethylformamide and dimethylacetamide, alcoholsincluding methanol and ethanol, and esters including ethyl acetate andmethyl acetate, and mixtures of such solvents, may be used as solventsfor the ozonolysis.

Reaction with ozone provides an ozonide involving the C₃ -C₄ double bondof the 3-butenoate group. The ozonide is then reduced with a mildreducing agent to form the corresponding 4-chloro-3-oxobutyrate. Thereduction is carried out with any of the agents commonly used for thedecomposition of ozonides, including such agents as zinc or magnesium inthe presence of water or acetic acid, alkali metal bisulfites, sulfurdioxide, trimethylphosphite, stannous chloride, Raney nickel, dialkylsulfides and the like. Decomposition of the ozonide is accomplished bysimply adding an excess of the reducing agent to the mixture containingthe ozonide at a temperature from about -80° C. to about 0° C.

Finally, the desired 3-hydroxycephalosporin is obtained by reacting theoxobutyrate obtained above with mild mineral acid. Acids such ashydrochloric acid, sulfuric acid, sulfonic acids such as methanesulfonicacid and toluenesulfonic acid, and aqueous perchloric acid may be used,at temperatures from about 0° C. to about 50° C. The product has the Rand R¹ groups of the thiazolinoazetidinone of this invention as its sidechain and acid protecting group, respectively.

Thus, it will be understood that the range of 3-hydroxycephalosporinsprepared by the exercise of this invention is defined by the range ofthiazolinoazetidinones which has been discussed above. It is accordinglyunnecessary to elaborate further on the 3-hydroxycephalosporin products.

3-Hydroxycephalosporins obtained by the above process have been welldiscussed in U.S. Pat. No. 3,917,587, of Chauvette, which thoroughlyexplains the use of such compounds as intermediates in preparing anumber of useful antibiotics.

It will be understood that the cephalosporins which are prepared fromthe novel compounds of this invention have their carboxy groups, and anyamino or hydroxy groups which may be on the amido side chains, in theblocked or protected form. Antibiotic chemists will of course understandthat protecting groups must be removed before antibiotic use is made ofsuch compounds.

The following preparative examples are shown to assure that the readercan use the thiazalinoazetidinones of this invention in the process ofthis invention for preparing 3-hydroxycephalosporins.

EXAMPLE A 4-nitrobenzyl3-hydroxy-7-phenylacetamido-3-cephem-4-carboxylate

A portion of 4-nitrobenzyl (1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoate,prepared from 0.5 g. of the corresponding 3-methyl-3-butenoate, wasdissolved in 20 ml. of dichloromethane and 10 ml. of methanol. Thesolution was cooled to -78° C., and ozone was bubbled slowly through thesolution until it turned blue. The temperature was held constant, and0.5 g. of trimethylphosphite was added with stirring. The reactionmixture was then allowed to warm to ambient temperature, and wasevaporated under vacuum to obtain a foam. Twenty ml. of methanol and 10ml. of 1-normal hydrochloric acid were added to the foam, and themixture was stirred for 5 minutes at 40° C. The mixture was thenevaporated to dryness under vacuum, producing a foam which was analyzedby TLC and NMR, and found to consist in large part of the desiredproduct. The following δ values were observed on the NMR spectrum.2.53-1.70(q); 2.7(m); 4.4(q); 6.66(d); 5.03(d); 6.37(s); 6.68(2d)

Infrared analysis as a Nujol mull showed absorptions at 3.04, 5.60 and6.0 microns.

EXAMPLE B 4-nitrobenzyl3-hydroxy-7-phenoxyacetamido-3-cephem-4-carboxylate

A 480 mg. portion of 4-nitrobenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-chloromethyl-3-butenoatewas dissolved in 25 ml. of dichloromethane and 25 ml. of methanol andcooled to -78° C. Ozone was bubbled through the solution with stirringuntil a blue color was observed, and then 1 g. of dimethyl sulfide wasadded. The reaction mixture was allowed to warm to ambient temperature,and was washed three times with saturated brine and dried over magnesiumsulfate. Ten ml. of methanol and 5 ml. of 1-normal hydrochloric acidwere added, and the mixture was stirred for 5 minutes at 40° C. It wasthen evaporated under vacuum to obtain a foam, which was analyzed andfound to consist in large part of the desired compound.

I claim:
 1. A process for preparing a compound of the formula ##STR6##wherein R is hydrogen,methoxy, C₁ -C₂ alkoxycarbonyl, C₁ -C₈ alkyl C₁-C₈ alkyl monosubstituted with protected hydroxy, C₁ -C₃ alkoxy orcyano, C₂ -C₈ alkenyl, C₂ -C₈ alkenyl monosubstituted with protectedhydroxy, C₁ -C₃ alkoxy or cyano, C₃ -C₈ cycloalkyl, C₃ -C₈ cycloalkylsubstituted with protected hydroxy, C₁ -C₃ alkoxy or cyano, ##STR7## R²is hydrogen, protected hydroxy, chloro, bromo, C₁ -C₃ alkyl, C₁ -C₃alkoxy, nitro or cyano; Y is oxygen or a carbon-carbon bond; R³ isprotected hydroxy, C₁ -C₄ alkyl or protected amino; m is 0-2; n is 0-2;R¹ is a carboxylic acid protecting group; provided that the 1- and5-position C--H bonds in the resulting thiazolinoazetidinone are in theα-position; comprising reacting a compound of the formula ##STR8##wherein the 1-and 5-position C--H bonds in the thiazolinoazetidinone arein the α-position, with molecular chlorine or t-butyl hypochlorite inthe presence of a C₁ -C₃ carboxylic acid; provided that, when thestarting compound is a thiazolinoazetidinone, and molecular chlorine isused, an epoxide is also present.
 2. A process of claim 1 for preparinga compound of the formula ##STR9## comprising reacting a compound of theformula ##STR10## with molecular chlorine or t-butyl hypochlorite in thepresence of a C₁ -C₃ carboxylic acid.
 3. A process of claim 1 forpreparing a compound of the formula ##STR11## comprising reacting acompound of the formula ##STR12## with molecular chlorine or t-butylhypochlorite in the presence of a C₁ -C₃ carboxylic acid; provided thatwhen molecular chlorine is used, a hydrochloric acid scavenger is alsopresent.
 4. A process of claim 1, 2 or 3 wherein t-butyl hypochlorite isused.
 5. A process of claim 4 wherein the reaction temperature is fromabout -20° C. to about 50° C.
 6. A process of claim 5 wherein thetemperature is from about -10° C. to the ambient temperature.
 7. Aprocess of claim 5 wherein the reaction solvent is a C₂ -C₈ alkyl ester.8. A process of claim 6 wherein the reaction solvent is a C₂ -C₈ alkylester.
 9. A process of claim 3 wherein molecular chlorine is used.
 10. Aprocess of claim 1 wherein 4-nitrobenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoateis reacted with t-butyl hypochlorite.
 11. A process of claim 1 wherein4-nitrobenzyl (1α,5α)-2-(3-benzyl-2-thia-6-oxo-4,7-diazabicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoateis reacted with t-butyl hypochlorite.
 12. A process of claim 1 whereinbenzyl (1α,5α)-2-(3-phenoxymethyl-2-thia-6-oxo-4,7-diazbicyclo[3.2.0]hept-3-en-7-yl)-3-methyl-3-butenoateis reacted with t-butyl hypochlorite.